Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer

Filippo Pietrantonio, Rosalba Miceli, Alessandra Raimondi, Young Woo Kim, Won Ki Kang, Ruth E. Langley, Yoon Young Choi, Kyoung-Mee Kim, Matthew Guy Nankivell, Federica Morano, Andrew Wotherspoon, Nicola Valeri, Myeong-Cherl Kook, Ji Yeong An, Heike I. Grabsch, Giovanni Fuca, Sung Hoon Noh, Tae Sung Sohn, Sung Kim, Maria Di BartolomeoDavid Cunningham, Jeeyun Lee, Jae-Ho Cheong, Elizabeth Catherine Smyth*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

135 Citations (Web of Science)

Abstract

PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.

PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI.

RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P <.001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).

CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.

Original languageEnglish
Pages (from-to)3392-3401
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number35
DOIs
Publication statusPublished - 10 Dec 2019

Keywords

  • MISMATCH REPAIR
  • PERIOPERATIVE CHEMOTHERAPY
  • ADJUVANT CHEMOTHERAPY
  • DOUBLE-BLIND
  • ADENOCARCINOMA
  • CAPECITABINE
  • GUIDELINES
  • CISPLATIN
  • SURVIVAL
  • THERAPY

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